PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. A major problem with HFpEF is severe exercise intolerance that leads to reduced quality of life. Although impaired cardiac output and marked left ventricle relaxation abnormalities are known to be present, drug therapies targeting cardiac function do not improve exercise tolerance, quality of life, or survival in HFpEF patients. Thus, a better characterization of HFpEF patients is warranted both at rest and during physical activities. Sympathetic overactivity is present in several cardiovascular disease states, and aside from contributing to high blood pressure (BP), this increase in sympathetic nerve activity (SNA) accelerates the progression of end organ damage that is independent of any rise in BP. Despite these critical problems, it remains unknown whether resting sympathetic overactivity is involved in the development and progression of HFpEF. Likewise, whether impairments in SNA control and resultant changes in the peripheral vasculature in resting and exercising muscle contribute to the severe exercise intolerance and poor prognosis present in HFpEF is unknown. We will examine the skeletal muscle metaboreflex, a key neural mechanism for increasing SNA with exercise. Also, sympathetically mediated vasoconstriction in non-exercising and exercising muscles will be investigated to determine whether the normal blunting of vasoconstriction in active muscle (i.e., functional sympatholysis) is impaired in HFpEF. All measures will be performed before and after exercise training regimens designed to minimize the marked increase in cardiac filling pressure during whole-body exercise known to be present in HFpEF. Overall, the global objective of Project 3 is to comprehensively investigate sympathetic neural mechanisms in HFpEF at rest and during exercise to seek an effective therapy for HFpEF patients. Aim 1 will determine whether HFpEF patients have enhanced SNA at rest, and whether exercise intolerance in HFpEF is associated with greater sympathetic reactivity and impaired functional sympatholysis. We will perform direct measures of SNA to skeletal muscle using microneurography, along with duplex Doppler ultrasound measures of peripheral blood flow, during a series of experimental tests to assess SNA control at rest and during exercise in patients with and without HFpEF. Aim 2 will determine whether whole-body training or single-leg knee extension differentially effects resting SNA, sympathetic reactivity, functional sympatholysis, and muscle metaboreflex activation in HFpEF patients. Patients will be randomly assigned to 16 weeks of either single-leg knee extension, where the heart is not limiting, or whole-body training with nitroglycerin treatment to attenuate the rise in cardiac filling pressure (1:1 ratio) with complete sympathetic assessments performed before and after training. Information gained from this research will lead to a comprehensive understanding of sympathetic neural mechanisms in patients with HFpEF and will provide important insight into potential therapeutic targets to improve quality of life and survival in HFpEF patients.